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Abstract
Brequinar is an immunosuppressant with the potential to be combined with cyclosporine
in synergistic combination therapy. The drug tends to accumulate when given daily
per os, and pharmacokinetic interaction with cyclosporine appears to enhance toxicity.
Analogues with similar immunosuppressive activity have been identified at Du Pont
Merck Pharmaceutical Co., that do not accumulate upon daily oral dosing in rats, and
hence could have an improved potential in combination treatment with cyclosporine.
We performed a toxicity study with brequinar and two brequinar analogues, administered
orally once daily for 4 weeks, either alone or in combination with cyclosporine (Neoral,
Novartis Pharma AG). In a first study relatively high doses were evaluated with cyclosporine
at non-toxic doses of 5 and 10 mg/kg/d. The maximum tolerated dose of brequinar alone
was estimated between 5 and 10 mg/kg/d; that of the analogues was estimated between
10 and 20 mg/kg/d, and above 20 mg/kg/d, respectively. In combination with cyclosporine
at 5 and 10 mg/kg/d, approximately a 2-fold reduction in the maximum tolerated dose
was observed. In a second study lower doses were evaluated in combination with cyclosporine
at 2.5 and 5 mg/kg/d. Also this study revealed increased toxicity of brequinar (analogues)
when given in combination with cyclosporine. The side effects observed were typical
for drugs in the brequinar class and included leukocytopenia and thrombocytopenia,
reduced body weight gain or body weight loss, thymic atrophy, cellular depletion of
bone marrow and splenic white pulp, and villous atrophy in jejunum. Concentrations
of brequinar (analogues) were determined in blood sampled 4 h after administration
at day 1, 14 and 21-28 of the experiment. There was a tendency for drug accumulation
in some groups treated with brequinar and cyclosporine. For one of the analogues at
a low dose, higher concentrations were measured in groups treated with combinations
of this compound and cyclosporine. We conclude that a potential synergism in immunosuppression
using combinations of brequinar (analogues) and cyclosporine can be complicated by
enhanced toxicity of the compounds. This indicates the need for a careful evaluation
of the therapeutic window in a combined treatment together with detailed pharmacokinetics.